TARGETED DISRUPTION OF THE C-FOS GENE DEMONSTRATES C-FOS-DEPENDENT AND C-FOS-INDEPENDENT PATHWAYS FOR GENE-EXPRESSION STIMULATED BY GROWTH-FACTORS OR ONCOGENES

The c-fos proto-oncogene is believed to play a pivotal role in transdu cing growth factor-mediated signals from the extracellular milieu into the nucleus. c-fos protein dimerizes with c-jun and related proteins and mediates transcription via AP-1 sites. Using c-fos-deficient mice generated through gene knockout techniques, we derived 3T3-type cell l ines from primary embryonic fibroblasts. The c-fos-deficient cells gro w normally under optimal culture conditions and show only a slight red uction in growth rate in low serum culture compared with control cells . They also express mRNA for most of the Fos and Jun family members at normal levels. The overall levels of AP-1 DNA binding activity are no rmal and several genes (c-jun, MCP1, metallothionein) known to contain functional AP-1 sites are expressed normally in the c-fos-deficient a nd control cells. In contrast, mRNA for the metalloproteases stromelys in (MMP-3) and type I collagenase (MMP-1), which are often induced by oncogenes and growth factors and have been implicated in tumor invasiv eness, cannot be induced by epidermal growth factor or platelet-derive d growth factor in c-fos-deficient cells. Transformation of mutant cel ls with polyoma middle T oncogene essentially restores wildtype levels of stromelysin expression, while transformation with v-src leads to o nly a weak induction of the metalloprotease. These results clearly dem onstrate that some AP-1-dependent genes require c-fos for full express ion while others do not; oncogenes may activate expression of metallop roteases via either fos-dependent or fos-independent mechanisms. These results also imply that c-fos may play an important regulatory role i n the invasive behavior of malignant tumors, independent of any role t his proto-oncogene might play in cell growth per se.